The surgical implantation of prosthetic devices (prostheses) into humans and other mammals has been carried out in recent years with increasing frequency. Such prostheses include, by way of illustration only, heart valves, vascular grafts, urinary bladders, heart bladders, left ventricular-assist devices, hip prostheses, silastic breast implants, tendon prostheses, and the like. They may be constructed from natural tissues, inorganic materials, synthetic polymers, or combinations thereof. By way of illustration, mechanical heart valve prostheses typically are composed of rigid materials, such as polymers, carbons, and metals, and employ a poppet occluder which responds passively with changes in intracardiac pressure or flow. Valvular bioprostheses, on the other hand, typically are fabricated from either porcine aortic valves or bovine pericardium; in either case, the tissue is pretreated with glutaraldehyde and then sewn onto a flexible metallic alloy or polymeric stent which subsequently is covered with a poly(ethylene terephthalate) cloth sewing ring covering. The assembled prostheses (often referred to in the literature as bioprostheses) are stored in 0.2 percent glutaraldehyde. Examples of reference of a more general nature include Helen E. Kambic et al., "Biomaterials In Artificial Organs," Chem. Eng. News, Apr. 14, 1986, pp. 31-48; and Frederick J. Schoen, "Pathology of Cardiac Valve Replacement," Chapter 8 in D. Morse et al., Editors, "Guide to Prosthetic Cardiac Valves," Springer-Verlag, N.Y., 1985, pp. 209-238.
Prostheses derived from natural tissues are preferred over mechanical devices because of certain significant clinical advantages. Tissue-derived prostheses generally do not require routine anticoagulation. Moreover, when they fail, they usually exhibit a gradual deterioration which can extend over a period of months, or even years. Mechanical devices, on the other hand, typically undergo catastrophic failure.
While any prosthetic device can fail because of mineralization, and especially calcification, this cause of prosthesis degeneration is especially significant for tissue-derived prostheses. Indeed, calcification has been stated to account for over 60 percent of the failures of cardiac bioprosthetic valve implants. Despite the clinical importance of the problem, the pathogenesis of calcification is incompletely understood. Moreover, there apparently is no effective therapy known at the present time.
References which discuss the calcification problem and its prevention include. among others. R. J. Levy et al., "Bioprosthetic Heart Valve Calcification: Clinical Features, Pathobiology, and Prospect for Prevention," CRC Review in Biocompatibility, 2, 147-187 (1986); Frederick J. Schoen et al., "Calcification of Bovine Pericardium Used in Cardiac Valve Bioprostheses," Am. J. Pathol., 123, 134-145 (1986); Robert J. Levy et al., "Inhibition by Diphosphonate Compounds of Calcification of Porcine Bioprosthetic Heart Valve Cusps Implanted Subcutaneously in Rats," Circulation, 71, 349-356 (1985); Gershon Golomb et al., "Inhibition of Bioprosthetic Heart Valve Calcification by Sustained Local Delivery of Ca and Na Diphosphonate via Controlled Release Matrices," Trans. Am. Soc. Artif. Intern. Organs, 32, 587-590 (1986); R. J. Levy et al., "Local Controlled-Release of Diphosphonates from Ethylenevinyllacetate Matrices Prevents Bioprosthetic Heart Valve Calcification" Trans. Am. Soc. Artif. Intern. Organs, 31, 459-463 (1985); and Frederick J. Schoen et al., "Onset and Progression of Experimental Bioprosthetic Heart Valve Calcification," Lab. Invest., 52, 523-532 (1985).
As a reading of many of the foregoing references will show, previous efforts at preventing the calcification of tissue-derived prostheses include:
(a) detergent pretreatment of the prosthesis;
(b) daily injection of a diphosphonate, such as 1-hydroxyethylidene diphosphonic acid;
(c) covalent binding of a diphosphonate, such as 1-hydroxy-3-aminopropane-1,1-diphosphonic acid, to bioprosthetic tissue proteins via residual aldehyde groups remaining after a glutaraldehyde pretreatment; and
(d) controlled-release, site-specific diphosphonate delivery by an osmotic pump or a controlled-release matrix, such as an ethylene-vinyl acetate copolymer, typically with 1-hydroxyethylidene diphosphonic acid or 1-hydroxy-3-aminopropane-1,1-diphosphonic acid as the diphosphonate. Suitable polymers typically include those disclosed in U.S. Pat. No. 4,378,224 to Moses J. Folkman et al.; see, also, U.S. Pat, Nos. 4,164,560 and 4,391,797, both to Moses J. Folkman and Robert S. Langer, Jr., neither of which appears to be directed to preventing calcification. For a similar disclosure which also does not appear to be directed at preventing calcification of implanted prostheses, see U.S. Pat. No. 4,357,312 to Dean S. T. Hsieh and Robert S. Langer, Jr. In addition to the two diphosphonates mentioned [see, also, Krammsch et al., Circ. Res., 42, 562-571, (1978)], other anticalcification agents which apparently are suitable for controlled-release applications include calcium channel blockers such as nifedipine [Henry et al., J. Clin. Invest., 68. 1366-1369 (1981)]; calcium chelating agents such as ethylenediamine-tetraacetic acid [Wartman et al., J. Atheroscler, Res., 7, 331-341 (1967)]; ionic antagonists such as lanthanum trichloride [Kramsch, supra]; thiophene compounds [Krammsch, supra]; and phosphocitrate analogues such as 2-aminotricarballylate.
As a variation of method (c), above, pretreatments of fixed natural tissue prostheses which apparently do not involve covalent binding are known. Several representative references are described below.
U.S. Pat. No. 4,402,697 to Elisabeth M. Pollock and David J. Lent describes a pretreatment using a solution of a water-soluble phosphate ester such as sodium dodecyl hydrogen phosphate.
A similar pretreatment using a solution of a water-soluble quaternary ammonium salt such as dodecyltrimethylammonium chloride is described in U.S. Pat, No. 4,405,327 to Elisabeth M. Pollock.
Finally, U.S. Pat, No. 4,323,358 to David J. Lentz and Elisabeth M. Pollock describes a pretreatment using a solution of a water-soluble salt of a sulfated higher aliphatic alcohol, such as sodium dodecyl sulfate.
While such methods were capable of lowering bioprosthetic tissue calcification, they are not free from difficulties. For example, detergent pretreatment, while having a short-term effectiveness, does not appear to be a viable approach for the long-term inhibition of tissue calcification. Diphosphonate injection at effective levels is accompanied by severe untoward effects on bone and overall somatic growth. The use of an osmotic pump requires the subdermal surgical implantation of the pump, and the long-term supply of the anticalcification agent administered by the pump is an issue which must be addressed. The long-term administration of an anticalcification agent also is an issue with controlled-release methods. In addition, the glutaraldehyde pretreatment used with all cardiac bioprostheses apparently facilitates prosthesis tissue calcification.
Thus, there is a pressing need for a more effective method for reducing or preventing the calcification of prostheses.